GB2616153A - Preparation method for exosome-loaded polymer for use in oral colon-targeting drug delivery - Google Patents
Preparation method for exosome-loaded polymer for use in oral colon-targeting drug delivery Download PDFInfo
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- GB2616153A GB2616153A GB2307931.2A GB202307931A GB2616153A GB 2616153 A GB2616153 A GB 2616153A GB 202307931 A GB202307931 A GB 202307931A GB 2616153 A GB2616153 A GB 2616153A
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- 229920000642 polymer Polymers 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 210000001808 exosome Anatomy 0.000 title claims abstract description 17
- 238000012377 drug delivery Methods 0.000 title abstract description 4
- SWPMTVXRLXPNDP-UHFFFAOYSA-N 4-hydroxy-2,6,6-trimethylcyclohexene-1-carbaldehyde Chemical compound CC1=C(C=O)C(C)(C)CC(O)C1 SWPMTVXRLXPNDP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 210000002901 mesenchymal stem cell Anatomy 0.000 claims abstract description 21
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 claims abstract description 4
- 229920001661 Chitosan Polymers 0.000 claims abstract description 4
- 229920002581 Glucomannan Polymers 0.000 claims abstract description 4
- 229940046240 glucomannan Drugs 0.000 claims abstract description 4
- 241001312219 Amorphophallus konjac Species 0.000 claims abstract description 3
- 235000001206 Amorphophallus rivieri Nutrition 0.000 claims abstract description 3
- 229920002752 Konjac Polymers 0.000 claims abstract description 3
- 235000010485 konjac Nutrition 0.000 claims abstract description 3
- 239000000252 konjac Substances 0.000 claims abstract description 3
- 239000006228 supernatant Substances 0.000 claims description 31
- 238000005119 centrifugation Methods 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims description 18
- 239000002953 phosphate buffered saline Substances 0.000 claims description 18
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 15
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 15
- 239000002244 precipitate Substances 0.000 claims description 11
- 238000000502 dialysis Methods 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 8
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000001085 differential centrifugation Methods 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 6
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 238000009777 vacuum freeze-drying Methods 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000012228 culture supernatant Substances 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 238000005538 encapsulation Methods 0.000 abstract description 2
- 230000008439 repair process Effects 0.000 abstract description 2
- 238000013268 sustained release Methods 0.000 abstract description 2
- 239000012730 sustained-release form Substances 0.000 abstract description 2
- 238000013329 compounding Methods 0.000 abstract 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract 1
- 239000003833 bile salt Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 210000004051 gastric juice Anatomy 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000003232 mucoadhesive effect Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 3
- 238000001338 self-assembly Methods 0.000 description 3
- 239000012679 serum free medium Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 229920006318 anionic polymer Polymers 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229920006317 cationic polymer Polymers 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- NBGAYCYFNGPNPV-UHFFFAOYSA-N 2-aminooxybenzoic acid Chemical class NOC1=CC=CC=C1C(O)=O NBGAYCYFNGPNPV-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010061819 Disease recurrence Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000001731 descending colon Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-O ethylaminium Chemical compound CC[NH3+] QUSNBJAOOMFDIB-UHFFFAOYSA-O 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000001599 sigmoid colon Anatomy 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000004876 tela submucosa Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
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- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
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Abstract
A preparation method for an exosome-loaded self-assembled polymer for use in oral colon-targeting drug delivery. The polymer is formed by compounding chitosan quaternary ammonium salt (HTCC), oxidized konjac glucomannan (OKGM), and a mesenchymal stem cell-derived exosome (MSCs-EXO) by means of layer-by-layer (LBL) wrapping and LBL encapsulation. The polymer has certain biocompatibility, stability, safety, anti-inflammatory, and sustained release performance, and can be used as a drug-carrying system to carry the exosome so as to repair an ulcerous part.
Description
PREPARATION METHOD FOR EXOSOME-LOADED POLYMER FOR USE IN ORAL COLON-TARGETING DRUG DELIVERY
TECHNICAL FIELD
[0001] The present disclosure relates to a preparation method for exosome-loaded polymer for use in oral colon-targeting drug delivery, and belongs to the field of biomedicine
BACKGROUND
[0002] Ulcerative colitis (UC) is a chronic and nonspecific intestinal inflammatory disease. UC lesions mainly involve the mucosa and submucosa of the sigmoid colon and rectum, and may also extend to the descending colon or even the entire colon. The clinical manifestations of UC mainly include diarrhea, mucopurulent feces, abdominal pain and other symptoms. UC generally occurs in late adolescence and early adulthood, with an average age of onset of 17 to 40 years. UC still has unclear etiology, and is prone to recurrent attacks. Moreover, the UC has a long course of disease, is protracted and unhealed, shows a carcinogenic tendency, and is generally accompanied by a variety of extraintestinal symptoms. Therefore, the World Health Organization (WHO) has identified UC as one of the modem incurable diseases.
[0003] At present, there is no standardized operation for the surgical treatment of UC. Drug treatment in traditional Chinese medicine generally takes the form of retention enema administration. In Western medicine, the treatment is mainly conducted with drugs such as aminosalicylic acids, corticosteroids, and immunosuppressants. Existing traditional drugs for treating UC generally face short duration of drug effect and non-sustainable anti-inflammatory effects. These traditional drugs are also prone to disease recurrence and poor targeting, which are easy to cause some adverse reactions.
[0004] Therefore, there is an urgent need to develop an exosome (EX0)-loaded polymer for colon-targeted oral administration, which has high safety, desirable stability, durable anti-inflammatory properties, and strong targeting. This polymer may show a broad market prospect for the treatment of UC.
SUMMARY
[0005] To achieve the above purpose, the present disclosure provides a preparation method of exosome (EX0)-loaded polymer for colon-targeted oral administration. In the present disclosure, N-(2-hydroxyl)propyl -3 -tri m ethyl ammonium chitosan chloride (H TCC) and oxidized konj ac glucomannan (OKGM) are used as an outer shell, and an EXO-loaded polymer for colon-targeted oral administration is wrapped through layer-by-layer (LBL) self-assembly. In this way, an LBL-self-assembled and EXO-loaded polymer system for colon-targeted oral administration may be obtained, which has high safety, desirable stability, durable anti-inflammatory properties, and strong targeting. The polymer systems are useful in the treatment of UC.
[0006] The present disclosure provides a preparation method of an EXO-loaded polymer for colon-targeted oral administration, including the following steps: 100071 (1) collecting a culture supernatant of mesenchymal stem cells (MSCs), and extracting an EXO by differential centrifugation; 100081 (2) adding periodate as an oxidant into an aqueous solution of konjac glucomannan (KGM), stirring to conduct a reaction, adding ethylene glycol, collecting a supernatant after conducting dialysis and solid-liquid separation, followed by freeze-drying to obtain oxidized KGM (OKGM); 100091 (3) dissolving the OKGM obtained in step (2) and N-(2-hydroxyl)propy1-3-trimethyl ammonium chitosan chloride (HTCC) in a phosphate-buffered saline (PBS) separately to obtain an OKGM solution and an HTCC solution; [0010] (4) subjecting the HTCC solution obtained in step (3) and the EXO obtained in step (1) to constant rotation for 20 min to 30 min, washing with the PBS, conducting centrifugation, and collecting a precipitate to obtain an (MSCs-EXO)-HTCC polymer; and [0011] (5) subjecting the (MSC5-EX0)-HTCC polymer obtained in step (4) and the OKGM solution obtained in step (3) to constant rotation for 20 min to 30 min, washing with the PBS, and conducting centrifugation to obtain an (MSCs-EXO)-(HTCC/OKGM) polymer, where [0012] steps (4) and (5) are repeated to prepare a layer-by-layer self-assembled polymer loaded with the MSCs for colon-targeted oral administration, namely an (MSC5-EX0)-(HTCC/OKGM)" polymer, and n is a number of wrapping layers.
[0013] In one embodiment, in step (1), the supernatant of the MSCs is a cell supernatant collected when third-generation MSCs are fused to 70% to 80%, and then cultured for 48 h with a serum-free medium.
[0014] In one embodiment, the MSC is a kind of pluripotent stem cell with self-renewal and multi-lineage differentiation abilities [0015] In one embodiment, in step (1), the differential centrifugation specifically includes: conducting centrifugation on the supernatant of the MSCs at 300 g to 500 g for 10 min to 15 min, and collecting a supernatant I; conducting centrifugation on the supernatant I at 1800 g to 2000 g for 10 min to 15 min, and collecting a supernatant II; conducting centrifugation on the supernatant II at 10000 g to 11000 g for 60 min to 70 min, and collecting a supernatant III; conducting centrifugation on the supernatant ET at 100000 g to 110000 g for 60 min to 70 min, and collecting an EXO precipitate, and resuspending the EXO precipitate in an appropriate amount of PBS, conducting centrifugation at 100000 g to 110000 g for 60 mm to to 70 mm, and collecting an obtained precipitate to obtain a purified EXO.
[0016] In one embodiment, in step (I), the differential centrifugation is conducted at 4°C.
[0017] In one embodiment, a preparation method of the OKGM specifically includes: dissolving 5 g of a KGM powder into 500 mL of deionized water by stirring, adding 10 mL of a 0.5 mol/L sodium periodate aqueous solution dropwise, and stirring in the dark at 40°C for 4 h; adding 10 mL of the ethylene glycol to a resulting reaction mixture and stirring for 2 h to neutralize unreacted periodate; conducting dialysis on a resulting solution using a dialysis membrane with a molecular weight cut-off (MWCO) of 12000 to 14000 for 3 d until an obtained dialysate does not have an iodate; subjecting a resulting reaction product to centrifugation at 2,500 r/min for 20 min, collecting a supernatant, and conducting vacuum freeze-drying to obtain the OKGM; and storing the obtained OKGM in a desiccator for later use.
[0018] In one embodiment, in step (3), the HTCC and the OKGM each are dissolved in the PBS at a final concentration of 0.01 mg/mL to 1.0 mg/mL [0019] In one embodiment, in steps (4) and (5), the washing with the PBS is conducted 2 to 3 times at a pH value of 7.2 to 7.4.
[0020] In one embodiment, the EXO and the HTCC solution are at a mass-to-volume ratio of (200-500) pg (1-3) mL; and the EXO is dissolved in the PBS.
[0021] In one embodiment, the OKGM solution and the HTCC solution are at a volume ratio of (1-3):(1-3).
[0022] In one embodiment, steps (4) and (5) are repeated preferably 1 to 3 times most preferably 2 times, to prepare an (MSCs-EXO)-(IITCC/OKGM)2 polymer.
[0023] The present disclosure further provides an LBL-self-assembled and MSCs-loaded polymer for colon-targeted oral administration prepared by the preparation method.
[0024] The present disclosure further provides a drug or a food including the LBL-selfassembled and MSCs-loaded polymer for colon-targeted oral administration.
[0025] The present disclosure further provides use of the LBL-self-assembled and MSCs-loaded polymer for colon-targeted oral administration in preparation of a drug for treating UC.
[0026] The present disclosure has the following beneficial effects: [0027] (1) In the present disclosure, the self-assembled polymer (MSC5-EX0)-(HTCC/OKGM),, prepared by LBL self-assembly has better biocompatibility, stability, safety, anti-inflammation properties, and sustained-release performances.
[0028] (2) In the present disclosure, the HTCC and the OKGM may release MSCs-EXO in a slow-controlled manner. Through homing properties of the MSCs-EXO, the regeneration and repair of ulcer tissues may be effectively promoted.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0029] The present disclosure is further described in detail through the following examples, but it should be understood that the present disclosure is not limited by the following contents.
[0030] Stability test: uncoated EXO and LBL-coated EXO are placed in a simulated bile solution and a simulated gastric juice, and then treated in a water bath at 37°C for 2 h. After 2 h, the EXOs are collected by centrifugation, washed twice and then tested for structural integrity. It is mainly observed whether a membrane structure of the EXO is complete.
[0031] Mucoadhesive ability assay: freshly isolated porcine small intestines are washed and sectioned. The LBL-coated or uncoated EXOs are labeled with specific fluorescence, pre-fixated on an inner wall of the small intestine, incubated at 37°C for 1 h, and then analyzed using 1VIS imaging.
[0032] Example 1
[0033] (1) Extraction of MSCs-derived EXO: when third-generation MSCs were fused to 70% to 80%, the MSCs were cultured in a serum-free medium for 48 h, and a cell supernatant was collected. The EXO was extracted by differential centrifugation, specifically: at 4°C, centrifugation was conducted on the supernatant of the MSCs at 300 g for 10 min, and a supernatant I was collected; centrifugation was conducted on the supernatant I at 2000 g for 10 min, and a supernatant II was collected; centrifugation was conducted on the supernatant II at 10000 g for 70 min, and a supernatant III was collected; centrifugation was conducted on the supernatant III at 100000 g for 70 min, and an EXO precipitate was collected; and the EXO precipitate was resuspended in an appropriate amount of PBS, centrifugation was conducted at 100000 g for 70 min, and an obtained precipitate was collected to obtain a purified EXO.
[0034] (2) Synthesis of OKGM: 5 g of a KGM powder was dissolved into 500 mL of deionized water by stirring, 10 mL of a 0.5 mol/L sodium periodate aqueous solution was added dropwise, and stirred in the dark at 40°C for 4 h. 10 mL of the ethylene glycol was added to a resulting reaction mixture and stirred for 2 h to neutralize unreacted periodate. Dialysis was conducted on a resulting solution using a dialysis membrane with a molecular weight cut-off (MWCO) of 12000 to 14000 for 3 d until an obtained dialysate did not have an iodate. A resulting reaction product was subjected to centrifugation at 2,500 r/min for 20 min, a supernatant was collected, and vacuum freeze-drying was conducted to obtain the OKGM; and dried OKGM was stored in a desiccator for later use.
[0035] (3) Synthesis of a self-assembled polymer (MSCs-EXO)-(HTCC/OKGM)11: the HTCC and the OKGM were dissolved in PBS at a final concentration of 0.1 mg/mL A cationic polymer HTCC and the EXO were mixed at a constant slow speed and a room temperature for 30 min, and washed 2 to 3 times to obtain an (MSCs-EXO)-HTCC polymer. An anionic polymer OKGM and the MSCs-HTCC were mixed at a constant slow speed and a room temperature for 30 min to obtain a self-assembled polymer (MSCs-EX0)-(HTCC/OKGM).
100361 Step (3) was repeated 1 to 2 times to obtain a self-assembled polymer (MSCs-EX0)- (HTCC/OKGM)2 and a self-assembled polymer (MSCs-EXO)-(l respectively.
100371 The (MSCs-EXO)-(HTCC/OKGM), (MSCs-EX0)-(HTCC/OKGM)2, and (MSCsEX0)-(HTCC/OKGM)3 were tested for stability and mucoadhesive properties, respectively.
100381 Stability test: the membrane structure of (MSCs-EXO)-(HTCC/OKGM) is destroyed in simulated gastric juice after two hours, which is not enough to protect EXOs from bile salts or gastric acid. However, the (MSC5-EX0)-(HTCC/OKGM)2 can still prevent acid and bile salt erosion for 2 h when being exposed to simulated gastric juice or simulated bile salt solution at 37°C. It is seen that the polymer had desirable stability. The (MSC5-EX0)-(HTCC/OKGM)3 have better stability.
100391 The experimental results of mucoadhesive ability assay shows that for the (IVISC5-EX0)-(HTCC/OKGM)2: after 1 h, the level of EXO wrapped in LBL can be detected is nearly three times higher than that of bare EXO. After 2 h, the EXO level can still be more than two times higher. Within 6 h, the level of EXO wrapped in LBL is significantly higher than that of the bare EXO. After 12 h, the difference gradually decreases due to the saturation of EXO. It is seen that LBL-encapsulated (MSC5-EX0)-(HTCC/OKGM)2 have a stronger mucoadhesive ability and can stay in the intestinal tract for a longer time. However, the time required for the release of (MSCs-EXO)-(HTCC/OKGM)3-encapsulated EXOs is prolonged, with a release delay of more than 4 h.
[0040] Example 2
100411 (1) Extraction of MSCs-derived EXO: when third-generation MSCs were fused to 70% to 80%, the MSCs were cultured in a serum-free medium for 48 h, and a cell supernatant was collected. The EXO was extracted by differential centrifugation, specifically: at 4°C, centrifugation was conducted on the supernatant of the MSCs at 300 g for 15 min, and a supernatant I was collected; centrifugation was conducted on the supernatant I at 1,800 g for 15 min, and a supernatant H was collected; centrifugation was conducted on the supernatant 11 at 11000 g for 60 min, and a supernatant III was collected; centrifugation was conducted on the supernatant III at 110000 g for 60 min, and an EXO precipitate was collected; and the EXO precipitate was resuspended in an appropriate amount of PBS, centrifugation was conducted at 110000 g for 60 min, and an obtained precipitate was collected to obtain a purified EXO.
[0042] (2) Synthesis of OKGM: 5 g of a KGM powder was dissolved into 500 mL of deionized water by stirring, 10 mL of a 0.5 mol/L sodium periodate aqueous solution was added dropwise, and stirred in the dark at 40°C for 4 h. 10 mL of the ethylene glycol was added to a resulting reaction mixture and stirred for 2 h to neutralize unreacted periodate. Dialysis was conducted on a resulting solution using a dialysis membrane with a molecular weight cut-off (MWCO) of 12000 to 14000 for 3 d until an obtained dialysate did not have an iodate. A resulting reaction product was subjected to centrifugation at 2,500 r/min for 20 min, a supernatant was collected, and vacuum freeze-drying was conducted to obtain the OKGM; and dried OKGM was stored in a desiccator for later use.
100431 (3) Synthesis of a self-assembled polymer (MSCs-EXO)-(HTCC/OKGM)": the HTCC and the OKGM were dissolved in PBS at a final concentration of 0.5mg/mL A cationic polymer HTCC and the EXO were mixed at a constant slow speed and a room temperature for 30 mm, and washed 3 times to obtain an (MSCs-EXO)-HTCC polymer. An anionic polymer OKGM and the MSCs-HTCC were mixed at a constant slow speed and a room temperature for 30 min to obtain a self-assembled polymer (MSCs-EX0)-(HTCC/OKGM).
[0044] Step (3) was repeated 1 time to obtain a self-assembled polymer (MSCs-EX0)-(HTCC/OKGM)2.
[0045] After detection, it is found that the self-assembled polymer (MSC5-EX0)-(HTCC/OKGM)2 can still prevent acid and bile salt erosion for 2 h when being exposed to simulated gastric juice or simulated bile salt solution at 37°C. It is seen that the polymer have desirable stability and delayed the release of EX0s.
100461 Comparative Example 1 [0047] Comparative Example I was the EXO directly extracted from step (1) of Example 1 without subsequent encapsulation.
[0048] The test results are as follows: when being exposed to the simulated gastric juice at 37°C, the common, unwrapped HTCC/OKGM EXO have a damaged structure.
[0049] Comparative Example 2 [0050] In this comparative example, other steps were the same as those in Example 1, but the KGM was not oxidized. According to the method of Example 1, the KGM and the HTCC were directly used for self-assembly.
[0051] The studies find that the above two components can not be self-assembled, because the KGM aqueous solution has viscosity and poor fluidity, and subsequent experiments are failed. 100521 Comparative Example 3 [0053] When 1-1TCC had a concentration of less than 0.01 mg/mL, the HTCC was not sufficiently positively-charged to support the binding to the EXO. When the HTCC had a concentration of greater than 1 mg/mL, the HTCC showed certain cytotoxicity-to the EXO. 100541 Although the present disclosure has been disclosed as above in preferred examples it is not intended to limit the present disclosure. Those skilled in the art may make various variations and modifications without departing from the spirit and scope of the present disclosure. Therefore, the protection scope of the present disclosure should be subject to that defined by the claims.
Claims (10)
- WHAT IS CLAIMED IS: I. A preparation method of an exosome (EXO)-loaded polymer for colon-targeted oral administration, comprising the following steps: (1) collecting a culture supernatant of mesenchymal stem cells (MSCs), and extracting an EXO by differential centrifugation; (2) adding periodate as an oxidant into an aqueous solution of konjac glucomannan (KGM), stirring to conduct a reaction, adding ethylene glycol, conducting dialysis and solid-liquid separation and collecting a supernatant, and conducting freeze-drying to obtain oxidized KGM (OKGM); (3) dissolving the OKGM obtained in step (2) and N-(2-hydroxyl)propy1-3-trimethyl ammonium chitosan chloride (FITCC) in a phosphate-buffered saline (PBS) separately to obtain an OKGM solution and an HTCC solution; (4) subjecting the HTCC solution obtained in step (3) and the EXO obtained in step (1) to constant rotation for 20 min to 30 min, washing with the PBS, conducting centrifugation, and collecting a precipitate to obtain an (MSCs-EXO)-FITCC polymer; and (5) subjecting the (MSCs-EXO)-HTCC polymer obtained in step (4) and the OKGM solution obtained in step (3) to constant rotation for 20 min to 30 min, washing with the PBS, and conducting centrifugation to obtain an (MSCs-EXO)-(1-1TCC/OKGM) polymer; wherein steps (4) and (5) are repeated to prepare a layer-by-layer self-assembled polymer loaded with the MSCs for colon-targeted oral administration, namely an (MSCs-EX0)-(HTCC/OKGM)" polymer, and n is a number of wrapping layers.
- 2. The preparation method according to claim 1, wherein a preparation method of the OKGM specifically comprises: dissolving 5 g of a KGM powder into 500 mL of deionized water by stirring, adding 10 mL of a 0.5 mol/L sodium periodate aqueous solution dropwise, and stirring in the dark at 40°C for 4 h; adding 10 mL of the ethylene glycol to a resulting reaction mixture and stirring for 2 h to neutralize unreacted periodate; conducting dialysis on a resulting solution using a dialysis membrane with a molecular weight cut-off (MWCO) of 12000 to 14000 for 3 d until an obtained di alysate does not have an iodate; subjecting a resulting reaction product to centrifugation at 2,500 r/min for 20 min, collecting a supernatant, and conducting vacuum freeze-drying to obtain the OKGM; and storing the obtained OKGM in a desiccator for later use.
- 3. The preparation method according to claim 1, wherein in step (3), the Errcc and the OKGM each are dissolved in the PBS at a final concentration of 0.01 mg/mL to 1.0 mg/mL
- 4. The preparation method according to claim 1, wherein in steps (4) and (5), the washing with the PBS is conducted 2 to 3 times at a pH value of 7.2 to 7.4.
- 5. The preparation method according to claim 1, wherein the EXO and the HTCC solution are at a mass-to-volume ratio of (200-500) pg: (1-3) mL.
- 6. The preparation method according to any one of claims 1 to 5, wherein the OKGM solution and the HTCC solution are at a volume ratio of (1-3):(1-3).
- 7. The preparation method according to claim 1, wherein steps (4) and (5) are repeated 1 to 3 times.
- 8. An EXO-loaded polymer for colon-targeted oral administration prepared by the preparation method according to any one of claims 1 to 7.
- 9. A drug comprising the EXO-loaded polymer for colon-targeted oral administration according to claim 8.
- 10. Use of the EXO-loaded polymer for colon-targeted oral administration according to claim 8 in preparation of a drug for treating ulcerative colitis (UC).
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